ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1591T>G (p.Phe531Val) (rs4988350)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573125 SCV000666233 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000573125 SCV000909777 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
Counsyl RCV000662403 SCV000784822 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000482354 SCV000571519 uncertain significance not provided 2016-08-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1591T>G at the cDNA level, p.Phe531Val (F531V) at the protein level, and results in the change of a Phenylalanine to a Valine (TTT>GTT). This variant was observed in at least one patient with hereditary breast or ovarian cancer, who was known to be BRCA1/2 negative (Rutter 2003). BRIP1 Phe531Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Valine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Phe531Val occurs at a position that is conserved across species and is located in the helicase domain (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Phe531Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206417 SCV000259479 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 531 of the BRIP1 protein (p.Phe531Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 219552). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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